The invention relates to compositions for the treatment and prevention of transmethylation disorders, preferably neurological and pathopsychological diseases.
It has been documented that neurological symptoms are associated with abnormally high levels of homocysteine in the blood (hyperhomocysteinemia or homocysteinuria). Investigations indicate that hyperhomocysteinemia contributes to microcephaly, mental retardation severe psychomotor retardation, convulsions, apneic spells, and even death. In several patients with methylenetetrahydrofolate reductase deficiency, which is one of the reasons for homocysteine accumulation, demyelination of the brain and subacute combined degeneration of the spinal cord was reported. Results of several studies have also shown that defective methylenetetrahydrofolate reductase and elevated homocysteine level are risk factors for neural tube defects such as spina bifida and anencephaly. Furthermore, elevated homocysteine levels have been found in amniotic fluid of pregnant women having fetuses with neural tube defects. The existence of a linear connection between the homocysteine level of mother and fetus has been reported.
In the human body, homocysteine is formed from methionine. In a simplified description methionine is condensed with adenosine triphosphate to produce S-adenosylmethionine and the latter is converted to S-adenosylhomocysteine. S-Adenosylhomocysteine is rapidly metabolised to homocysteine which is an important branch-point metabolite. It can be regenerated back to methionine, it can be converted to S-adenosylhomocysteine or it can enter the trans-sulfuration-pathway by reaction to cystathionine.
In the past, it has been the aim of several studies to treat hyperhomocysteinemia, i.e. to lower the elevated homocysteine levels. It is known that betaine and choline, which is converted to betaine by oxidation, may act as methylating agents. For example, the enzyme-catalyzed reaction between betaine and homocysteine in the human organism leads to the formation of methionine and dimethylglycine and the treatment with betaine is known to be efficient in lowering homocysteine concentrations. Other attempts included the supplementation of vitamins like vitamin B6, vitamin B12 or usual multivitamins, vitamin B6 in combination with a methionine restriction, methylcobalamine, folic acid, folic acid together with vitamins B6 and B12, folate, and occasionally folate in combination with vitamin B6, vitamin B12, choline or betaine (M. R. Malinow, J. Nutr. 126 (1996) 1238-1243).
However, the effectiveness of the previously applied compositions was not satisfactory. The treatment approach has not been linked to the complexity of the transmethylation metabolism.
The invention had the object of providing new compositions for the treatment and prevention of transmethylation disorders, preferably neurological and pathopsychological diseases, which improve the treatment significantly.
It has now been found that this object can be achieved with compositions which comprise one or more active ingredients and, optionally, one or more natural substances, solid, liquid and/or semiliquid excipients or auxiliaries, characterized in that the active ingredients consist of
a) a component A consisting of one or more phosphatidylserines,
b) a component B consisting of one or more methyl transporters, and
c) a component C consisting of one or more compounds selected from methyl and methylene donors,
provided that phosphatidylserines and compounds with methyl transporting properties do not form part of component C.
The new compositions according to the invention also affect the whole area of cardiovascular dysfunctions.
The invention furthermore relates to compositions for the treatment and prevention of diseases associated with hyperhomocysteinemia.
Phosphatidylserines, which are donors of one carbon groups, are naturally occurring phospholipid components of cellular membranes. These biomembranes are involved in a number of vital processes, such as nerve cell differentiation, activation and renewal, nerve transmitter production, ion transport etc. Phosphatidyiserines are found in all cells and organs of the body, but they are most concentrated in nerve cells of the brain and are essential for several brain functions, e.g. for the conduction of nerve impulses and the production, storage and release of neurotransmitters.
It has been documented that the oral supplementation with 200 to 300 mg of phosphatidylserines per day for 2 to 6 months improves brain metabolism and benefits cognitive functions such as memory, thinking, learning, and the ability to concentrate especially in aging people and in patients with certain neurological and pathopsychological conditions. The effectiveness of phosphatidylserines in the treatment of senile dementia, Parkinson""s disease epilepsy, depression, and age-associated memory impairment has also been demonstrated in several studies.
Posphatidylserines appear to make pro-homeostatic contributions and provide metabolic support to a wide range of brain functions. It has been assumed that phosphatidylserines are able to stimulate glucose metabolism in the brain and also increase the number of neurotransmitter receptor sites.
Phosphatidylserines are not abundant in common foods, but they have a good availability by oral route and are suitable as dietary supplement. They appear in the blood at about 30 minutes after oral administration and are able to cross the blood-brain barrier. Phosphatidylserines reach the brain within minutes after being absorbed.
As mentioned above, it has been documented that many neurological symptoms are associated with hyperhomocysteinemia. According to the invention it has now been found that an elevated homocysteine level is a sign of the inadequate methyl pool involving both methyl donors and methyl transporters. Therefore, the homocysteine level in the human body may be used as an indicator of the state of the transmethylation metabolism in certain cases.
In the human body, one-carbon or C1 groups exist in several oxidation states. These groups include methyl groups, methylene groups, methylidyne groups, carbonyl groups, formyl groups, hydroxymethyl groups, and carboxyl groups. Practically, these groups can be divided into groups at the oxidation level of methanol, formaldehyde, and formate Exemplary sources of the methyl group (methanol oxidation level) are methionine, adenosylmethionine, methylated glycines, and choline. The sources of methylene group (formaldehyde oxidation level) are serine and glycine. One of the sources of the group at the formate oxidation level is e.g. histidine. All of these one-carbon groups form the so-called one-carbon pool and participate in many important reactions. As the methyl group is biochemically the most ubiquitous, the one-carbon pool is often referred to as the methyl pool.
The metabolic events of methyl groups are usually specified as transmethylation, whereas the involved molecules are called transmethylators. Depending upon their function during the metabolic events, the transmethylators are classified as methyl donors, methyl transporters, and methyl acceptors. Methyl donors are e.g. methionine, S-adenosylmethionine, choline, methylglycine (sarcosine), dimethylglycine, and trimethylglycine (betaine). Methyl transporters are e.g. tetrahydrofolates which are derived from folic acid and methylcobalamine and adenosylcobalamine, which are coenzymes derived from vitamin B12. Methyl acceptors include all nucleic acids, proteins, most of them enzyme proteins, phospholipids (components of biomembranes), and many biological amines, which serve as neurotransmitters in many cases.
The properly functioning methylation of these four classes of acceptor molecules is of importance for their biochemical activity. The methylation of the nucleic acids assures their structure stability and their accurate genetic performance. The methylation of the enzyme proteins ensures their specificity and efficiency and prevents the accumulation of intermediary metabolites. The methylation of the phospholipids provides an optimal cytomembrane functionality and the methylation of the biological amines guarantees their specificity and effectiveness.
A decrease of the pool of methyl donors and/or of methyl transporters may lead to transmethylation disorders. Impairments of the methylation (also referred to as demethylations) of one or more components of the four methyl acceptor classes may occur and dysfunctions of these methyl acceptors may be the consequence. Metabolic dysfunctions and diseases may result.
Major neurological and pathopsychological diseases associated with hyperhomocysteinemia are depression, premature old age or senilism, dementia, Pick""s disease, metabolic myelopathy, peripheral neuropathy, neural tube defects, e.g. anencephaly, spina bifida or encephalocoele, gait disturbances, and muscle weakness. The invention furthermore relates to compositions for treatment and prevention of these diseases.
The expression xe2x80x9cmethyl donorxe2x80x9d (component C) stands for substances which are able to deliver methyl groups to transporter molecules. Important methyl donors are e.g. choline and S-adenosylmethionine.
Choline is required for the biosynthesis of essential membrane phospholipids. It is a precursor for the biosynthesis of the neurotransmitter acetylcholine and also is an important source of labile methyl groups. Since the late 1970""s the relation between choline levels and the synthesis of acetylcholine was extensively studied. It was found that the administration of choline caused significant sequential elevations in serum choline, brain choline, and brain acetylcholine levels. Recently, much attention has been paid to the effect of supplemental choline upon brain function, i.e. upon the enhancement of acetylcholine synthesis and release. Choline supplementation has been advocated as a means to prevent the decline in acetylcholine production and to enhance cholinergic transmission.
Choline was used as a therapeutic agent for suppression of the major side-effects of antipsychotic drugs such as tardive dyskenesia and for treatment of several other diseases that are thought to involve cholinergic neurons. These disorders include both brain diseases such as mania and memory loss and peripheral diseases such as myastenic syndromes.
S-Adenosylmethionine serves as a precursor in the biosynthesis of polyamines. It is synthesized from adenosyltriphosphate and L-methionine by methionine-adenosyltransferase. Recently, the effect of oral S-adenosylmethionine in doses of 400 mg on plasma levels of several methionine metabolites such as the demethylated product S-adenosylhomocysteine, homocysteine, and methionine was investigated. It is known that disorders of homocysteine metabolism contribute to cerebral, peripheral and coronary vascular disease. Administration of S-adenosylmethionine produces significant improvements in patients with depressive syndromes.
The expression xe2x80x9cmethylene donorxe2x80x9d (component C) stands for substances which are able to deliver methylene groups to transporter molecules. A known methylene donor is e.g. serine, a component of the phosphatidylserines.
The expression xe2x80x9cmethyl transporterxe2x80x9d (component B) is used for substances which are able to transfer methyl groups to acceptor molecules. Therefore, the methyl transporters have to contain a transferable methyl group or they have to be able to remove a transferable methyl group from the donor molecules. Alternatively, they have to be able to remove another group from the donor molecules, but a group that may be converted to a transferable methyl group during the metabolic events or they have to contain such a group. For example, it is known that tetrahydrofolate may be converted to the 5-methyl derivative, which is able to transfer its methyl group to acceptor molecules. Furthermore, it is documented that the 5-methyl, 5-formyl, 10-formyl, 5,10-methylene, and 5,10-methenyl derivatives of tetrahydrofolate may be converted enzymatically into each other, i.e. each of these compounds may be converted to the 5-methyl derivative. Therefore, all of the abovementioned derivatives of tetrahydrofolate are methyl transporters within the meaning of the present invention.
If component C of the inventive compositions consists only of methylene donors, component B has to comprise at least one methyl transporter which is able to remove methylene groups from the methylene donors and convert these methylene groups to transferable methyl groups.
On principle, all known phosphatidylserinesxe2x80x94their physiologically acceptable salts includedxe2x80x94may be used as constituents of component A of the inventive compositions. The phosphatidylserines may contain saturated and/or unsaturated fatty acid groups, e.g. groups selected from palmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid groups.
Preferred methyl transporters (component B) are selected from dihydrofolic acid, tetrahydrofolic acid, 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid, 10-formyltetrahydrofolic acid, 5,10-methylenetetrahydrofolic acid, 5,10-methenyltetrahydrofolic acid or their physiologically acceptable salts. Particularly preferred methyl transporters are derivatives of L- or (S)-glutamic acid and are selected from (6S)-tetrahydrofolic acid, 5-methyl-(6S)-tetrahydrofolic acid, 5-formyl-(6S)-tetrahydrofolic acid, 10-formyl-(6R)-tetrahydrofolic acid, 5,10-methylene-(6R)-tetrahydrofolic acid, 5,10-methenyl-(6R)-tetrahydrofolic acid or their physiologically acceptable salts. Among these the methyl transporter 5-methyl-(6S)-tetrahydrofolic acid (which is also referred to as L-5-methyltetrahydrofolic acid) or a physiologically acceptable salt thereof is especially preferred. L-5-methyltetrahydrofolic acid penetrates all organs of the human body.
Preferred methyl or methylene donors (component C) are selected from betaine, dimethylglycine, sarcosine, methionine, S-adenosylmethionine, choline, serine, and their physiologically acceptable salts.
The physiologically acceptable salts of the phosphatidylserines, methyl donors and methylene donors can be obtained by converting a base of these compounds with an acid into the associated acid addition salt. Acids which yield physiologically harmless salts are e.g. inorganic acids, for example sulfuric acid, nitric acid, hydrochloric acid, phosphoric acids, such as orthophosphoric acid, organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid or nicotinic acid.
Furthermore, the physiologically acceptable salts of the phosphatidylserines, methyl donors and methylene donors can be obtained by converting an acid of these compounds with a base into one of its physiologically harmless metal salts or ammonium salts. Suitable salts in this context are, in particular, the sodium, potassium, magnesium, calcium and ammonium salts, and also substituted ammonium salts, for example the dimethyl-, diethyl- or diisopropylammonium salts, monoethanol-, diethanol- or diisopropylammonium salts, cyclohexyl- or dicyclohexylammonium salts or dibenzylethylenediammonium salts, and also, for example, salts with arginine or lysine.
The physiologically acceptable salts of the methyl transporters are selected from alkali metal or alkaline earth metal salts, preferably from sodium, potassium, magnesium, and calcium salts.
If amino acids mentioned above or below may occur in more than one enantiomeric form, all of these forms and also mixtures thereof are included (e.g. the DL-forms). Preferably, the amino acids mentioned have (S)- or (L)-configuration even if this is not stated explicitly.
In preferred compositions according to the invention the molar ratio of component A: component B: component C is from 500:1:30,000 to 1:1:300.